Fentanyl suspension-based silicone adhesive formulations and devices for transdermal delivery of fentanyl

ABSTRACT

Silicone adhesive formulations are provided, in which fentanyl particles are suspended one or more a solvated silicone adhesives. The formulations can be used for manufacturing improved, matrix-type transdermal devices for administering fentanyl.

CROSS-REFERENCE TO RELATED APPLICATIONS

The instant application is a continuing application of currently pendingU.S. patent application Ser. No. 11/743,411 filed May 2, 2007 and is acontinuing application of currently pending U.S. patent application Ser.No. 11/723,111 filed Mar. 16, 2007. Both the '411 and '111 applicationsare continuations of U.S. patent application Ser. No. 11/438,391, filedMay 23, 2006, which is a continuation of U.S. patent application Ser.No. 10/283,355, filed Oct. 30, 2002. Each of the '411, '111, '391, and'355 applications are incorporated by reference in their entirety.Applicants claim benefit and priority under 35 U.S.C. §120.

FIELD OF THE INVENTION

The present invention relates generally to the field of transdermal drugdelivery. More particularly, the present invention relates to fentanylsuspension-based, silicone pressure sensitive adhesive formulations andtheir use in making devices for improved transdermal delivery offentanyl.

BACKGROUND OF THE INVENTION

A pressure sensitive adhesive is a material that adheres to a surfacewith slight pressure and releases from the surface with negligibletransfer of the adhesive to the surface. Silicone pressure sensitiveadhesives in particular have been used for transdermal drug delivery,which involves administering a drug by adhering a drug-containing deviceor patch to a patient's skin.

One type of transdermal patch is a polymer matrix or monolithic devicein which the active agent is contained in a polymer matrix film throughwhich the active agent diffuses to the skin. Such patches are preferredbecause they are relatively simpler to manufacture and more comfortableto wear compared to reservoir-type devices. Transdermal patches having amonolithic polymer film layer in which the active agent is contained aredisclosed in U.S. Pat. No. 4,839,174, as well as in U.S. Pat. Nos.4,908,213 and 4,943,435.

Fentanyl is an opioid analgesic which, in clinical settings, exerts itsprinciple pharmacologic effects on the central nervous system. Itsprimary actions of therapeutic value are analgesia and sedation, and itis indicated for the management of chronic pain in patients who requireopioid analgesia for pain that is typically unmanageable by lessermeans. In particular, fentanyl is used clinically for the relief ofacute postoperative and chronic cancer pain.

Transdermal patches containing silicone pressure sensitive adhesivecompositions are described in U.S. Pat. No. 5,232,702 (Pfister et al.),WO 00/33812 (Miranda et al.), WO 96/40085 (Mantelle et al.), and U.S.Pat. No. 5,603,947, all fully incorporated herein by reference.

U.S. Pat. No. 5,232,702 describes silicone pressure sensitive adhesivescontaining (i) a silicone fluid, (ii) a silicate resin, and (iii) acohesive strengthening agent. In one embodiment, the pressure sensitiveadhesive includes a high molecular weight polydimethylsiloxane as thesilicone fluid. Organic solvents disclosed as suitable for dissolvingthe silicone fluid and the silicate resin include aromatics such astoluene and xylene; aliphatics such as heptane and hexane; chlorinatedsolvents such as 1,1,1-trichloroethane and trichlorotrifluoroethane;fluorocarbons such as Freon 113; aliphatic esters such as ethyl acetate;and mixtures thereof. Example D describes how transdermal adhesivematrix-type patches were prepared containing 17-beta estradiol, a skinpenetration enhancer (PGML), a high silanol containing silicone pressuresensitive adhesive, and calcium stearate as the cohesive strengtheningagent. Two different high silanol containing adhesives were used, bothof which were prepared in a xylene solvent by homogenously mixing asilicate resin, xylene, and a silicone fluid. The mixture was thenheated, stripped of non-volatile content, and eventually redissolved inhexane to a non-volatile content of 50 wt %. The final 17-betaestradiol-containing adhesive solution was cast onto a polyester releaseliner, allowed to air dry, and then laminated onto a polyester backingfilm.

WO 00/33812 describes a transdermal patch for administering a volatileliquid drug, such as nicotine. The transdermal patch contains a backinglayer, a pressure sensitive silicone adhesive layer and a pressuresensitive acrylic adhesive layer containing the drug, and a removablerelease liner layer. The silicone adhesive layer is prepared bydissolving a silicone adhesive in hexane. WO 00/33812 reports (at p. 6)that other solvents, such as heptane and toluene, are not suitablebecause they require higher processing temperatures and thus result inmore drug degradation and/or evaporation during coating and drying.

WO 96/40085 describes transdermal matrix patches for administeringdrugs, such as selegiline, nitroglycerin and nicotine, which are liquidat normal room temperature. WO 96/40085 suggests making a monolithicmatrix of the drug in an adhesive by mixing one or more polymericadhesives, preferably polyacrylate and polysiloxane, and the drug in avolatile solvent, casting the mixture, and evaporating the solvent.Examples of volatile solvents provided are isopropanol, ethanol, xylene,toluene, hexane, cyclohexane, heptane, ethyl acetate and butyl acetate.

Similarly, U.S. Pat. No. 5,603,947 describes in Example 1 the use ofheptane to cast a silicone adhesive layer in nicotine patches.

In both of the above references, the drugs are dissolved in the siliconeadhesives prior to casting.

Transdermal patches containing fentanyl in a silicone pressure sensitiveadhesive are also known in the art, as described, for example, in U.S.Pat. Nos. 4,588,580 (Gale et al.) and 5,186,939 (Cleary et al.), alsofully incorporated herein by reference.

U.S. Pat. No. 4,588,580 describes in Example 6a fentanyl-containingmonolithic patch that was made using Dow Corning amine resistantsilicone adhesive and silicone medical fluid having 10 and 20 percentfentanyl base dispersed therein.

U.S. Pat. No. 5,186,939 describes a laminated composite foradministering fentanyl transdermally, including an adhesive-drugreservoir layer comprising fentanyl dissolved in an amine-resistantpolydimethylsiloxane. Example 1 describes that a fentanyl-containingpressure sensitive adhesive composition was prepared consisting of 1.8%fentanyl base, 4% permeation enhancer (PGML), 2.0% silicone oil (DowCorning Medical Fluid) and 92.5% amine resistant polydimethylsiloxane(Dow Corning X7-2900) dissolved in trichlorotrifluoroethane (freon) toprovide a 50% solution.

In addition, a fentanyl-containing, reservoir-type transdermal patch asapproved by the FDA is described in the 2002 Physician's Desk Reference.Duragesic® is a rectangular transparent patch comprising a protectiveliner and four functional layers. Proceeding from the outer surfacetoward the surface adhering to the skin, these layers are: 1) a backinglayer of polyester film; 2) a drug reservoir of fentanyl and alcohol USPgelled with hydroxyethyl cellulose; 3) an ethylene-vinyl acetatecopolymer membrane that controls the rate of fentanyl delivery to theskin surface; and 4) a fentanyl containing silicone adhesive.

The present invention is believed to offer improvements and advantagesover prior fentanyl-containing transdermal devices.

SUMMARY OF THE INVENTION

One aspect of the invention is a fentanyl-containing, silicone pressuresensitive adhesive formulation comprising a blend of fentanyl suspendedin a solvated silicone pressure sensitive adhesive. The selected solventis one that can substantially or fully solvate or dissolve the adhesivewhile keeping the fentanyl suspended in the solvated adhesive.

The formulation of the invention can be made by blending fentanylparticles directly with one or more solvated silicone adhesives to forma suspension of fentanyl particles in the solvated adhesive(s).Alternatively, the formulation can be made by first combining thefentanyl particles with a silicone fluid to wet the particles and form aslurry, which slurry then can be blended with the solvated siliconeadhesive(s) to also form a suspension of fentanyl particles in thesolvated adhesive(s).

The above formulations are useful for making monolithic devices forimproved transdermal administration of fentanyl.

Thus, another aspect of the invention is a method for making a laminate,which is useful for making a monolithic patch for transdermaladministration of fentanyl. The method comprises the steps of:

a) selecting a solvent that can substantially or fully solvate asilicone adhesive while keeping fentanyl particles, when blended withthe solvated adhesive, suspended in the solvated adhesive;

b) blending fentanyl particles with one or more silicone adhesives whichare solvated with the above solvent, to form a blend formulation inwhich fentanyl particles are suspended in the solvated adhesives;

c) casting the blend formulation onto a support material; and

d) removing the solvent, to produce a laminate containing the supportmaterial and a fentanyl suspension-containing adhesive layer.

In a preferred embodiment, the blend formulation formed in step (b) isfurther treated prior to the casting step.

The blend formulation preferably is cast onto a backing layer or releaseliner. The solvent can be removed during drying by evaporation from theadhesive layer. The laminate can be further processed to produce amonolithic device containing a backing layer, fentanylsuspension-containing adhesive layer, and release liner.

A further aspect of the invention then is a monolithic patch foradministering fentanyl transdermally to an individual comprising: (a) abacking layer substantially impervious to the fentanyl to beadministered transdermally; (b) a fentanyl-containing adhesive layer incontact with at least a portion of the backing layer, the adhesive layerbeing cast from a formulation comprising a blend of fentanyl particlessuspended in one or more solvated silicone adhesives; and (c) aremovable release liner in contact with the adhesive layer.

A still further aspect of the invention is a method for administeringfentanyl transdermally to an individual in need of such administration,comprising applying to the skin of the individual a monolithic patchcomprising: (a) a backing layer substantially impervious to the fentanylto be administered transdermally; and (b) a fentanyl-containing adhesivelayer in contact with the backing layer, the adhesive layer being castfrom a formulation comprising a blend of fentanyl particles suspended inone or more solvated silicone adhesives.

In a preferred embodiment, the selected solvent is heptane.

An adhesive layer according to the present invention was found toprovide improved transdermal release of fentanyl, as well as improvedadhesion of transdermal devices to skin. Also with the presentinvention, greater amounts of fentanyl can be delivered from the patchthan from solution-based matrix patches, thus leaving lower residualamounts of fentanyl in the patch after administration.

The present invention provides non-invasive sustained analgesia forperiods ranging from 24 hours to 168 hours, and preferably for 72 hoursto 84 hours (about 3 to 3½ days) or 72 hours to 168 hours (about 3 to 7days). Preferred embodiments of the invention include 3 day (72 hours)and 7 day (168 hours) patches.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is an elevational cross-sectional view of an embodiment of atransdermal medical device or patch in accordance with the invention.

FIG. 1B is an elevational cross-sectional view of an embodiment of asuspension-cast laminate of the invention.

FIG. 2 is a graph comparing in vitro transdermal delivery rates offentanyl for a 3-day suspension blend-based device of the invention, a3-day solution blend-based recrystallized device, and a Duragesictransdermal patch.

FIG. 3 is a graph comparing in vitro transdermal delivery rates offentanyl for a 7-day suspension blend-based device of the invention anda 7-day solution blend-based recrystallized device.

FIG. 4 is a graph comparing rates of fentanyl release for a 3-daysuspension blend-based device of the invention and a 3-day solutionblend-based recrystallized device.

FIG. 5 is a graph comparing rates of fentanyl release for a 7-daysuspension blend-based device of the invention and a 7-day solutionblend-based recrystallized device.

FIG. 6 is a graph showing the in vitro transdermal delivery rate offentanyl for 7 days from a suspension blend-based device of theinvention made without silicone fluid.

FIG. 7 is a graph showing the in vitro rate of fentanyl release from asuspension blend-based device of the invention made without siliconefluid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides formulations in which fentanyl particlesare suspended in a solvent-based silicone adhesive. The fentanylsuspension is produced by blending fentanyl particles with asolvent-based silicone adhesive. The selected solvent is one that cansubstantially or fully solvate or dissolve the silicone adhesive. Theselected solvent also must be suitable for preventing highconcentrations, e.g., greater than about 1.0% w/w (dry weight), offentanyl particles from dissolving in the solvated adhesive.

The total amount of fentanyl need not be suspended in the solvatedadhesive, thus allowing for instances when a portion of the fentanyl isdissolved in the solvated adhesive. In the discussion below, the focuswill be on “suspended particles” or “suspensions” of fentanyl, but it isto be understood that this does not exclude those embodiments in which asmall proportion of the fentanyl is dissolved in the solvated adhesive.

The solvent preferably is heptane, but also may be selected from otherorganic solvents, preferably closely related aliphatic solvents suchhexane and octane, for example, as long as the selected solvent exhibitsthe above-described dissolution features.

The formulations made in accordance with the present invention are usedto manufacture improved devices for delivering fentanyl transdermally,particularly monolithic transdermal patches. The devices may bemanufactured by casting the formulation onto a support material such asa backing layer or release liner to form a fentanylsuspension-containing adhesive layer, which can be further processed tomake a transdermal patch for delivering fentanyl.

Thus, to manufacture a device having the advantages of the presentinvention, one must first produce a formulation comprising a liquidblend of fentanyl particles suspended in a solvated silicone adhesive,which formulation then is subsequently processed to make the device.Alternative methods for producing or achieving a fentanylsuspension-containing adhesive layer according to the invention may beapparent to persons skilled in the art, and these alternative methodsthus also fall within the scope of the present invention.

In a preferred embodiment, one or more silicone pressure sensitiveadhesives is dissolved in heptane, while fentanyl particles are mixedwith a silicone fluid to form a slurry. The slurry of fentanyl insilicone fluid then is blended with a portion of the heptane-solvatedsilicone adhesive and passed through a high shear colloid mill or othermixing device to form a suspension. This suspension then is blended withthe remaining heptane-solvated silicone adhesive to form the final (andmore dilute) suspension. The composition then is cast onto a releaseliner and passed through an oven(s) to drive off the heptane. A backingfilm then is laminated onto the dried adhesive matrix.

In another preferred embodiment, the device or patch is produced bycasting a blend of heptane-solvated adhesive(s) and suspended (solid)fentanyl alkaloid particles. A slurry is produced by mixing fentanyldirectly with a portion of the heptane-solvated silicone adhesive(s). Nosilicone fluid is used. This slurry then is passed through a colloidmill or similar mixing device to form a suspension. This suspension thenis blended with the remaining heptane-solvated silicone adhesive(s) toform the final (and more dilute) suspension that can be cast onto arelease liner and passed through an oven to drive off the heptane. Abacking film then is laminated onto the dried adhesive matrix.

The silicone pressure sensitive adhesive preferably is solvated in about20% to about 50% heptane, and more preferably in about 30% heptane. Inaddition to contributing to formation of a fentanyl suspension, otheradvantages of using heptane include decreased toxicity as compared toother solvents, which include, for example, toluene, xylene and otheraromatics generally.

In a preferred embodiment, fentanyl particles are suspended uniformly inthe solvated silicone adhesive as small particles, preferablycrystalline particles.

In the present invention, it is believed that as fentanyl leaves thesystem during the course of wear, the suspended drug in the systemdissolves and replenishes the delivered drug. The present invention as aresult maintains a level thermodynamic activity (driving force) for thedrug over long periods of wear. No other type of reservoir is known tohave such capability. The present invention thus permits long periods ofdelivery without requiring that a large excess of fentanyl be present.

Suitable silicone adhesives include pressure sensitive adhesives madefrom silicone polymer and resin. The polymer to resin ratio can bevaried to achieve different levels of tack. Examples of useful siliconeadhesives which are commercially available include the standard BioPSA®series (7-4400, 7-4500 and 7-4600 series) and the amine compatible(endcapped) BioPSA® series (7-4100, 7-4200 and 7-4300 series)manufactured by Dow Corning. Preferred heptane-solvated siliconeadhesives include BIO-PSA® 74201, BIO-PSA® 74301, and BIO-PSA® 7-4501.

In one embodiment, in which silicone medical fluid is used, thepreferred amount of silicone pressure sensitive adhesive used is fromabout 75% to about 99% w/W (dry weight), and more preferably from about80% to about 90% w/w (dry weight).

In another embodiment, in which one or more different silicone adhesivesmay be used, optionally in the presence of silicone medical fluid, thepreferred combined amount of silicone pressure sensitive adhesive isfrom about 75% to about 99% w/w (dry weight), more preferably from about85% to about 95% w/w (dry weight), and most preferably about 91% w/w(dry weight).

Preferred silicone fluids include high molecular weightpolydimethylsiloxane, Dimethicone NF (Dow 360 Silicone Medical Fluid,100 cSt and other viscosities). Preferred amounts of silicone fluid arefrom about 0% w/w to about 25% w/w (dry weight), more preferably fromabout 2% w/w to about 10% w/w (dry weight), even more preferably fromabout 5% w/w to about 8.5% w/w (dry weight), and most preferably about6.5% w/w (dry weight). Preferred viscosities of the silicone fluid arefrom about 20 cSt to about 350 cSt, and most preferably about 100 cSt.

Alternatives to silicone fluid, such as mineral oil, also may be usedand are within the scope of the invention.

The width or thickness of the adhesive layer (shown as 14 in each ofFIGS. 1A and 1B) is that width which provides at least sufficientadhesion of the device to the skin of the host. The width or thicknessalso may vary depending upon such factors as the amount of drug to bedelivered from the composition or adhesive layer and the desired wearperiod. The thickness of the adhesive layer will usually range fromabout 10 to 300 μm, more preferably 70 to about 140 μm. Expressedalternatively, the adhesive layer will be present at about 1 to about 30mg/cm², more preferably about 7 to about 14 mg/cm². Variations also canbe determined as a matter of routine experimentation by those ofordinary skill in the art. The width also need not be uniform and mayvary around the perimeter of the device, e.g., to provide a specificgeometric shape or to provide a tab for removal of a protective liner.

Fentanyl is administered preferably in the free base form. Fentanylalkaloid powder is available from Mallinckrodt. In another embodiment,an analgetically effective relative of fentanyl may be administered,including sufentanil, carfentanil, lofentanil, and afentanil. Thequantity of fentanyl contained in the adhesive layer is preferably thatquantity sufficient to provide a pharmaceutically or physiologicallyeffective dosage rate of the active agent to a host in need thereof. Thequantity of fentanyl also is sufficient to maintain at least a partialsuspension of the fentanyl in a solvated adhesive. This quantity can bereadily determined by those of ordinary skill in the art without undueexperimentation.

In one embodiment, preferred amounts are about 1% to about 10% w/w (dryweight), more preferably about 3% to about 7% w/w (dry weight), and mostpreferably about 4.0% w/w (dry weight) of fentanyl.

In another embodiment, preferred amounts are about 5% to about 15% w/w(dry weight), more preferably about 8% to about 12% w/w (dry weight),and most preferably about 9.1% w/w (dry weight) of fentanyl.

Preferred delivery rates will usually be in the range of about 5 toabout 250 μg/hour, more preferably about 10 μg/hour to about 100μg/hour, and most preferably about 25, 50, 75 and 100 μg/hour.

A flux enhancer to promote the penetration of the fentanyl through theskin may be included in the adhesive layer. Suitable enhancers includethose described in U.S. Pat. No. 4,573,966, including, monovalent,saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6to 12 carbon atoms such as cyclohexanol, lauryl alcohol and the like;aliphatic and cycloaliphatic hydrocarbons such as mineral oil;cycloaliphatic and aromatic aldehydes and ketones such as cyclohexanone;N,N-di(lower alkyl) acetamides such as N,N-diethyl acetamide,N,N-dimethyl acetamide, N-(2-hydroxyethyl) acetamide, and the like;aliphatic and cycloaliphatic esters such as isopropyl myristate andlauricidin; N,N-di(lower alkyl) sulfoxides such as decylmethylsulfoxide; essential oils, nitrated aliphatic and cycloaliphatichydrocarbons such as N-methyl-2-pyrrolidone and azone; salicylates,polyalkylene glycol silicates; aliphatic acids such as oleic acid andlauric acid, terpenes such as cineole, surfactants such as sodium laurylsulfate, siloxanes such as hexamethyl siloxane; mixtures of the abovematerials; and the like.

The backing layer (identified as 12 in each of FIGS. 1A and 1B) ispreferably a thin film or sheet. In some instances, because of the areaof skin to which the device is to be attached, the device, and thereforethe backing layer 12, may be opaque or colored for cosmetic reasons. Inone embodiment, it is a clear layer that is occlusive with respect tothe active agent or drug, printed matter thereon. The backing layer 12normally provides support and a protective covering for the device.

The backing layer 12 is preferably made of a material or combination ofmaterials that is preferably impermeable, or at least substantiallyimpermeable, to the adhesive layer and the fentanyl contained therein.

Suitable materials for the backing layer 12 include those known in theart for use with pressure sensitive adhesives. For example, the backinglayer 12 can comprise a polyolefin, including polyethylene; a polyester;multi-layer EVA film and polyester; polyurethane; or combinationsthereof. A preferred backing material is MEDIFLEX® 1000, a polyolefinmanufactured by Mylan Technologies, Inc. Other suitable materialsinclude, for example, cellophane, cellulose acetate, ethyl cellulose,plasticized vinyl acetate-vinyl chloride copolymers, ethylene-vinylacetate copolymer, polyethylene terephthalate, nylon, polyethylene,polypropylene, polyvinylidene chloride (e.g., SARAN),ethylene-methacrylate copolymer (Surlyn), paper, cloth, aluminum foiland polymer-metal composites.

The material that forms the backing layer 12 may be flexible ornon-flexible. Preferably, a flexible backing layer is employed toconform to the shape of the body member to which the device is attached.

In one embodiment, the medical device (10 in each of FIGS. 1A and 1B)contains a protective release liner (identified as 16 in each of FIGS.1A and 1B) attached to the device at the surface to be adhered to theskin, namely the fentanyl-containing adhesive layer. The release liner16 is removed before the device 10 is placed on the skin. The releaseliner 16 is thus made of a material(s) that permits the liner to beeasily stripped or peeled away from the adjacent pressure sensitiveadhesive layer. The release liner 16 may be made of the same materialssuitable for use in the backing layer 12 as discussed above. Suchmaterial is preferably made removable or releasable from the adhesivelayer, for example, by conventional treatment with silicon polymers,fluoropolymers (e.g., Teflon) or other suitable coatings on the surfacethereof. The removal of the device 10 from the release liner 16 may alsobe provided by mechanical treatment of the release liner 16, e.g., byembossing the release liner.

Suitable release liners include those known in the art for use withpressure sensitive adhesive compositions. For example, the release linercan comprise a fluorosilicone coated polyester. A preferred releaseliner is MEDIRELEASE® 2500, manufactured by Mylan Technologies, Inc., ora fluoropolymer-treated polyester, such as Scotchpak® 1022, manufacturedby 3M Pharmaceuticals/D.D.S. The release liner 16, however, can comprisevarious layers, including paper or paper-containing layers or laminates;various thermoplastics, such as extruded polyolefins, such aspolyethylene; various polyester films; foil liners; other such layers,including fabric layers, coated or laminated to various polymers, aswell as extruded polyethylene, polyethylene terephthalate, variouspolyamides, and the like.

In one embodiment, the release liner 16 includes a laminate of an outerfoil layer and an inner layer of plastic, such as polyethylene or thelike, which is rendered releasable not only by means of a siliconizedcoating, but which also includes an embossed or roughened surface.Embossment is described in U.S. Pat. No. 6,010,715 (Bertek), which isfully incorporated herein by reference.

In one embodiment of this invention, the patch further comprises afentanyl-free adhesive layer in between the backing layer 12 and thefentanyl-containing adhesive layer 14. This additional adhesive layerextends beyond at least a portion of the fentanyl-containing adhesivelayer to provide a further surface area that can adhere to the skin ofthe wearer, thereby enhancing the adhesive qualities of the device orpatch. The size and shape of the backing layer will be essentiallyco-extensive with the size and shape of this additional adhesive layer.This fentanyl-free adhesive layer can comprise any conventionaladhesive, such as a polyisobutylene or an acrylic acid polymer, such asalkyl acrylate or methacrylate polymers, as found in any of a variety ofcommercially available transdermal patches or tapes.

The compositions of this invention possess sufficient adhesiveproperties that once the release liner is removed and the composition isapplied to the skin the composition can remain in place for a period oftime sufficient to distribute the desired amount of the drug containedtherein with a low incidence of debonding.

One skilled in the transdermal art would readily recognize the possiblesizes of devices or patches in accordance with the invention. The patchsizes preferably vary depending on the desired delivery rates offentanyl, preferably increasing in size as the desired delivery rateincreases. Preferred delivery rates are from about 5 to about 300 μg/hr,more preferably about 50 to about 200 μg/hr, and most preferably about25, 50, 75 and 100 μg/hour. These delivery rates correspond to patchsizes of 1.25 to about 75 cm², more preferably about 12.5 to about 50cm², and most preferably 6.25, 12.5, 18.75, and 25 cm², respectively.

The device 10, once formed, may be kept sealed in an air-tight pouchprior to use. The device of the present invention is used in the samemanner as those devices which are conventional in the prior art. Inparticular, the release liner 16 attached to the skin-side surface ofthe adhesive layer 14 of the device 10 for contact with the skin ormucosa of the host is removed and such surface of the adhesive layer 14is applied to the desired area of the skin or mucosa.

The host or individual to which an active agent is administered by meansof the inventive device may be any host in which fentanyl has thedesired effect. The host may be, for example, a mammal such as a humanbeing, or any warm-blooded or cold-blooded animal. The advantage ofadministering fentanyl may be therapeutic or experimental. The device ofthis invention may also be used for any other advantageous purpose.

Various embodiments of the present invention were prepared and tested inaccordance with testing procedures recognized in the art. In particular,release of fentanyl from recrystallized laminates was compared tofentanyl release from suspension-cast laminates in accordance with theinvention.

Four active laminates as described in Table 3 were made and tested forin vitro transdermal delivery, in vitro rate of release, and Polykenprobe tack. In addition, the gross nature of the four blends wasqualitatively assessed. The results are summarized below.

Formulation Descriptions of Fentanyl from Recrystallized Vs.Suspension-Cast Laminates

TABLE 3 Fentanyl Blend Solvent Blend Lot # 4.0% w/w Heptane (30%)Suspension R6J0001 4.0% w/w Ethyl Acetate (41%) Solution 246P110C 9.5%w/w Heptane (30%) Suspension 246P114A 9.5% w/w Ethyl Acetate (55%)Solution 246P118A

In Vitro Transdermal Delivery of Fentanyl from Recrystallized Vs.Suspension-Cast Laminates

FIG. 2 shows the cumulative in vitro transdermal delivery of fentanylfrom laminates identical in content, but produced by differentprocedures. The lot R6J0001 was produced by casting a blend ofheptane-solvated silicone adhesive and suspended (solid) fentanylalkaloid particles. A slurry of fentanyl in 360 Medical Fluid(dimethicone NF) and a portion of the heptane-solvated silicone adhesivewere blended and passed through a high shear colloid mill to form asuspension. This suspension was then blended with the remainingheptane-solvated silicone adhesive to form the final (and more dilute)suspension that was cast onto a release liner and passed through ovensto drive off the heptane. The final step in this process was laminatinga backing film onto the dried adhesive matrix.

The recrystallized formulation (246P100C) was produced by casting ablend of ethyl acetate-solvated adhesive and dissolved fentanylalkaloid. In this process, the fentanyl was combined with the 360Medical Fluid and the ethyl acetate-solvated silicone adhesive. Thefentanyl dissolved completely to form a true solution. This solutionblend was then cast onto the release liner and dried in an oven,whereupon the fentanyl crystallized. The final step in this process alsowas laminating the backing film onto the dried adhesive matrix.

Table 4 shows the comparison of the above two formulations tested (whichare theoretically identical in their dry form).

TABLE 4 Residual Solvent Lot 360 Medical (Trace Number DescriptionAdhesive Fluid (100 cSt) Fentanyl quantities) R6J0001 ClinicalManufactured 89.5% w/w 6.5% w/w 4.0% w/w Heptane 6.25 cm² 25 μg/hr(7-4201) 246P110C Laboratory Recrystallized 89.5% w/w 6.5% w/w 4.0% w/wEthyl Acetate Laminate 4% Fentanyl (7-4202)

FIG. 2 shows that the 3-day suspension-cast formulation delivered invitro more fentanyl per unit time than the recrystallized formulation.

Table 5 shows a comparison of the (wet) composition of a suspensionblend formulation and the final (dry) composition of an adhesive matrixaccording to the invention.

TABLE 5 Component Wet (w/w) Dry (w/w) Fentanyl 2.86% 4.0% Bio-PSA ®7-4201 Silicone Adhesive 92.49% 90.5% 360 Medical Fluid (100 cSt) 4.65%6.5%

FIG. 3 shows the cumulative in vitro transdermal delivery of fentanylfrom 7-day patches, also identical in content, but produced by differentprocedures. Lot 246P114A was produced by casting a blend ofheptane-solvated silicone adhesive and suspended (solid) fentanylalkaloid particles. In this process, the fentanyl was wetted with the360 Medical Fluid and the resulting slurry combined with theheptane-solvated silicone adhesive to form a final suspension. Thissuspension was then cast onto the release liner and dried in an oven.The final step in this process was laminating the backing film onto thedried adhesive matrix.

The recrystallized formulation (246P118A) was produced by casting ablend of ethyl acetate-solvated adhesive and fentanyl. This blend wascreated by combining the fentanyl with the 360 Medical Fluid and theethyl acetate-solvated silicone adhesive. All of the fentanyl dissolvedin the blend. This blend was then cast onto the release liner and driedin an oven. The final step in this process was also laminating thebacking film onto the dried adhesive matrix.

Table 6 shows the compositions of the two above formulations (which aretheoretically identical in their dry form).

TABLE 6 Residual Lot 360 Medical Solvent (Trace Number DescriptionAdhesive Fluid (100 cSt) Fentanyl quantities) 246P114A LaboratorySuspension Blend 84.0% w/w 6.5% w/w 9.5% w/w Heptane Laminate 9.5%Fentanyl (7-4201) 246P118A Laboratory Recrystallized 84.0% w/w 6.5% w/w9.5% w/w Ethyl Acetate Laminate 9.5% Fentanyl (7-4202)

FIG. 3 shows that the 7-day suspension-cast and recrystallizedformulations were the same in terms of in vitro transdermal fentanyldelivery.

In another embodiment of the invention, FIG. 6 shows the cumulative invitro transdermal delivery of fentanyl from a 7 day patch in accordancewith the present invention. The lot R6J00014 was produced by casting ablend of heptane-solvated silicone adhesive(s) and suspended (solid)fentanyl alkaloid particles. A slurry was produced by mixing fentanyldirectly with a portion of the heptane-solvated silicone adhesive(s). Nosilicone fluid was used. This slurry was then passed through a colloidmill to form a suspension. This suspension was then blended with theremaining heptane-solvated silicone adhesive to form the final (and moredilute) suspension that was cast onto a release liner and passed throughovens to drive off the heptane. The final step in this process waslaminating a backing film onto the dried adhesive matrix. Table 7 showsthe final (dry) composition of the adhesive matrix.

TABLE 7 Component (w/w) g/m² Fentanyl 9.09% 10 Bio-PSA ® 7-4201 SiliconeAdhesive 45.455% 50 Bio-PSA ® 7-4301 Silicone Adhesive 45.455% 50

Table 8 shows a comparison of the (wet) composition of the suspensionblend formulation and the final (dry) composition of the adhesive matrixshown in Table 7.

TABLE 8 Component Wet (w/w) Dry (w/w) Fentanyl 6.54% 9.09% Bio-PS A ®7-4201 Silicone Adhesive 46.73% 45.455% Bio-PS A ® 7-4301 SiliconeAdhesive 46.73% 45.455%

Table 9 also shows a comparison of the (wet) composition of a suspensionblend formulation and the final (dry) composition of an adhesive matrix,according to another embodiment in which no silicone fluid was used.

TABLE 9 Component Wet (w/w) Dry (w/w) Fentanyl 6.85% 9.5% Bio-PSA ®7-4201 Silicone Adhesive 46.58% 45.25% Bio-PSA ® 7-4301 SiliconeAdhesive 46.58% 45.25%

The ratio of adhesives used together may be adjusted without undueeffort to improve adhesive properties, if necessary or desired.

Rate of Release of Fentanyl from Recrystallized Vs. Suspension-CastLaminates

FIG. 4 shows the rate of fentanyl release for the two lots R6J0001 and246P 110C tested for in vitro transdermal delivery.

FIG. 5 shows the rate of fentanyl release for lots 246114A and 246P118Atested for in vitro transdermal delivery.

FIG. 7 shows the rate of release for lot R6J0014 tested for in vitrotransdermal delivery.

The above results show that the recrystallized laminates (246P110C and246P118A) release fentanyl much faster than suspension-cast laminates(R6J0001, 246P114A and R6J0014) in accordance with the invention, i.e.,more than 80% of the fentanyl is released within the first hour from therecrystallized laminates. The above differences may be due to fentanylin the recrystallized laminates crystallizing at the release linersurface, which also may explain why the recrystallized laminates had nomeasurable tack, as shown below.

In contrast, in the suspension-cast laminates, fentanyl crystals werefound to be evenly distributed throughout the matrix, rather than onlyat the release liner surface.

Polyken Probe Tack of Recrystallized and Suspension-Cast Laminates

The suspension-cast fentanyl laminates were also found to possesssuperior adhesive properties, as compared with the solution-castlaminates. As a result, more thorough measurements of Polyken probe tackwere collected to quantitate any differences between the two processes(suspension-cast vs. solution-cast). Table 10 summarizes the results ofthe tack testing on these laminates.

TABLE 10 Formulation Process Lot # Tack (g/cm²) (4% fentanyl)Suspension-cast R6J0001 2335 (n = 4) (4% fentanyl) Recrystallized246p110C 0 (no adhesion to probe) (9.5% fentanyl) Suspension-cast246p114A 1499 (n = 6) (9.5% fentanyl) Recrystallized 246p118A 0 (noadhesion to probe)

Table 10 shows that the solution-cast laminates have no measurable tackcompared to the suspension-cast laminates.

Table 11 shows the results of tack testing for the 7 day patch (lotR6J0014)

TABLE 11 Polyken Probe Tack (g/cm2) 1451 ± 280

Photomicrographs were taken to compare qualitative observations oflaminates produced from either solution blends or suspension blends.

The overall composition of laminate pairs produced from solution andsuspension blends was the same, the only difference being the solventused to solvate the adhesive blend. As the solvent was removed from thesolution blends, the fentanyl crystallized.

In the suspension blend composition (R6J001), fentanyl particles weremore or less round and about 10 to 20 μm in diameter. Also present inthe laminates are some agglomerates (about 30 to 60 μm in diameter), butvery few single (rod-shaped) crystals.

In the solution blend composition (246p110c), very small crystalsappeared throughout the laminate (too small to accurately measure theirsize). Clearer, low-density spots were visible to the naked eye. Underthe microscope, these spots were found to have a relatively largecrystal-agglomerate in the middle (˜100 μm) surrounded by a crystal-freearea. It was hypothesized that a large, low-energy crystal grew at theexpense of the surrounding crystals. About 4-8 such agglomerates wereseen in each 10 cm² laminate sample. Therefore, the solution blendtended to produce a laminate containing larger, discrete crystallineparticles while the suspension blend produced a laminate with smaller,more evenly dispersed particles.

Two additional suspension blend and solution blend compositions weretested and compared. The overall composition of the laminates producedfrom the solution and suspension blends also was the same, the onlydifference being the solvent used to solvate the adhesive. As above,removal of the solvent from the solution blend caused the fentanyl tocrystallize.

In the 7-day suspension blend composition (246p114A), the appearance wassimilar to the analogous 3-day suspension laminate above (R6J0001). Inparticular, most of the fentanyl particles were round in shape with afew rod-shaped crystals at the adhesive-release liner interface.Particle and agglomerate sizes also were similar to those in the 3-daysuspension-cast laminate, although many more agglomerates were observed(as expected at a significantly higher drug load).

In the recrystallized 7-day blend composition (246p118A), the crystalshape and size was similar to the analogous 3-day solution-cast laminate(246p110C). However, as expected, many more agglomerates were observedin the 7-day laminates than in the 3-day laminate.

Devices made in accordance with the present invention are useful forinducing analgesia and sedation. Specific uses include the management ofchronic pain in patients who require opioid analgesia for pain, such asfor relief of acute postoperative and chronic cancer pain. Otherpossible uses include treatment of other chronic body pain, such as backpain and arthritis pain.

The invention is further illustrated by the following examples, whichare not intended to be limiting.

Example 1

Fentanyl free base (0.0245 kg) is uniformly dispersed in 360 MedicalFluid, 100 cSt (0.061 kg), in a glass jar with the help of aUltra-Turrax T8 dispersing unit for 20 minutes. This premix is addedslowly to heptane-solvated BIO-PSA® 7-4201 (0.751 kg), 70% w/w solidscontent, with continuous mixing utilizing a Glass-Col mixer. This ismixed for 20 minutes. Using a Warner-Mathis KTF coater, the mixture isthen coated onto a release liner (Scotchpak® 1022) and then dried at 78°C. for about 10 minutes to obtain a coat weight of 99.1 g/m². The driedfilm is then laminated onto a backing film (MediFlex® 1000). Patches ofappropriate size are then die-cut from the laminate prior to analyses.

Example 2

Fentanyl free base (3.20 g) and 360 Medical Fluid, 100 cSt (4.00 g) areadded in a 4 ounce glass jar. To this jar half of the pre-weighedheptane-solvated BIO-PSA® 7-4201 (103.34 g), 70.45% w/w solids content,is added. This mix is then homogenized with the help of a dispersingunit (D7801, Dottingen, TYP-1020 L) for 3 minutes. To this mixture theremaining half of the heptane-solvated BIO-PSA® 7-4201 is added. Thisblend is mixed with a simple lab blender for 3 minutes. Using a fixedknife, the blend is then coated onto a release liner (ScotchPak™ 1022)and then dried at 75° C. for 10 minutes to obtain a coat weight of90-100 g/m². The dried film is then laminated onto a backing film(Mediflex® 1000). Patches of appropriate size are then die-cut from thelaminate prior to analysis.

Example 3

Fentanyl free base (2.00 g) is homogenized in 360 Medical Fluid-100 cSt(5.00 g) in a 4 ounce glass jar with the help of a dispersing unit(D7801, Dottingen, TYP-1020 L) for 3 minutes. To this premixheptane-solvated BIO-PSA® 74201 (61.43 g), 70% w/w solids content, isadded. This blend is mixed with a simple lab blender for 3 minutes,Using a fixed knife, the blend is then coated onto a release liner(ScotchPak™ 1022) and then dried at room temperature for 5 minutes and70° C. for 10 minutes to obtain a coat weight of 90-100 g/m². The driedfilm is then laminated onto a backing film (Mediflex® 1000). Patches ofappropriate size are then die-cut from the laminate prior to analysis.

Example 4

Fentanyl free base (2.00 g) and 360 Medical Fluid-100 cSt (1.63 g) areadded in a 4 ounce glass jar. To this jar, half of the pre-weighedheptane-solvated BIO-PSA® 7-4201 (30.34 g), 70.45% w/w solids content,is added. This mix is then homogenized with the help of a dispersingunit (D7801, Dottingen, TYP-1020 L) for 3 minutes. To this mixture theremaining half of the heptane-solvated BIO-PSA® 7-4201 is added. Thisblend is mixed with a simple lab blender for 3 minutes. Using a fixedknife, the blend is then coated onto a release liner (ScotchPak™ 1022)and then dried at 75° C. for 10 minutes to obtain a coat weight of90-100 g/m². The dried film then is laminated onto a backing film(Mediflex® 1000). Patches of appropriate size are then die-cut from thelaminate prior to analysis.

Example 5

Fentanyl free base (3.17 g), 360 Medical Fluid-100 cSt (2.17 g), andheptane-solvated BIO-PSA® 7-4201 (39.74 g), 70.45% w/w solids content,are added in a 4 ounce glass jar. This mix then is homogenized with thehelp of a dispersing unit (D7801, Dottingen, TYP-1020 L) for 3 minutesto fully disperse fentanyl. Using a fixed knife, the blend is thencoated onto a release liner (ScotchPak™ 1022) and then dried at 72° C.for 10 minutes to obtain a coat weight of 90-100 g/m². The dried film isthen laminated onto a backing film (Mediflex® 1000). Patches ofappropriate size are then die-cut prior to analysis.

Example 6

Fentanyl free base (3.17 g), heptane-solvated BIO-PSA® 7-4201 [21.41 g,70.45% w/w solids content], and heptane-solvated BIO-PSA® 74301 [19.85g, 76.00% w/w solids content], are added in a 4 ounce glass jar. Thismix is then homogenized with the help of a dispersing unit (D7801,Dottingen, TYP-1020 L) for 3 minutes to fully disperse fentanyl. Using afixed knife, the blend is then coated onto a release liner (ScotchPak™1022) and then dried at 72° C. for 10 minutes to obtain a coat weight of110 g/m². The dried film then is laminated onto a backing film(Mediflex® 1000). Patches of appropriate size then are die-cut prior toanalysis.

Example 7

Fentanyl free base (12.73 g) and heptane-solvated BIO-PSA® 7-4301(181.82 g, 70.0% w/w solids content) were added to an 8 oz glass jar.This mixture was then homogenized with a dispersing unit (Vertishear, 20mm diameter shaft) for 3 minutes to fully disperse the fentanylparticles. Using a doctor blade, the blend was coated onto a releaseliner (ScotchPak™ 1022) and dried at 72° C. for 10 minutes to obtain acoat weight of 100-110 g/m². The dried film was then laminated onto abacking film (Mediflex® 1000). Patches of appropriate size were thendie-cut from the finished laminate to form the delivery systems.

The publications and other materials used herein to illuminate thebackground of the invention, as well as provide additional detailsrespecting the practice of the invention, are incorporated herein byreference to the same extent as if they were specifically andindividually indicated to be incorporated by reference.

While the invention has been disclosed by reference to the details ofpreferred embodiments of the invention, it is to be understood that thedisclosure is intended in an illustrative rather than a limiting sense,as it is contemplated that modifications will readily occur to thoseskilled in the art, within the spirit of the invention and the scope ofthe appended claims.

1. A monolithic transdermal patch comprising: (a) a backing layer havinginner and outer surfaces; and (b) a first adhesive layer having a firstsurface covering at least a portion of said inner surface of saidbacking layer, said adhesive layer comprising atherapeutically-effective amount of fentanyl in an adhesive, whereinless than 1% of said fentanyl can be dissolved in said adhesive whensaid adhesive is fully solvated with a solvent capable of fullysolvating or dissolving said adhesive. 2-20. (canceled)